Quinoline carboxylic acid derivatives

ABSTRACT

A quinolone carboxylic acid derivative having the following formula (1), ##STR1## wherein R 1  is a hydrogen atom, an alkyl group, an aralkyl group, an ester residual group which can be hydrolyzed in living bodies, R 2  is a hydrogen atom or an amino group which may be substituted by one or two lower alkyl groups, X is a hydrogen atom or a halogen atom, Y is CH 2 , O, S, SO, SO 2 , or N--R 3 , wherein R 3  is a hydrogen atom or a lower alkyl group, and Z is an oxygen atom or two hydrogen atoms; or a salt thereof; and an antimicrobial agent comprising the same. The compound exhibits a superior antimicrobial activity, especially against gram positive microorganisms, and is thus useful for the treatments and prevention of various infectious diseases in clinics.

This application is a continuation of application Ser. No. 07/842,191, filed as PCT/JP91/00954, Jul. 17, 1991, now abandoned.

TECHNICAL FIELD

The present invention relates to a novel quinolone carboxylic acid derivative and a salt thereof which exhibit excellent antimicrobial activity against both Gram positive and Gram negative microorganisms.

BACKGROUND ART

Synthetic antimicrobial agents such as nalidixic acid, piromidic acid, and the like are known as drugs for curing infectious diseases caused by Gram negative microorganisms. They exhibit, however, only deficient effects on intractable diseases such as pseudomoniasis and the like.

On the other hand, quinolone carboxylic acid derivatives substituted with a fluorine atom at 6 position, such as norfloxacin, ofloxacin, and cyprofloxacin, or quinolone carboxylic acid derivatives substituted with a chlorine atom at 8 position have been developed (Japanese Patent Laid-open (ko-kai) Nos. 225181/1986, 90183/1989) and clinically used because of their strong antimicrobial activity.

These conventional synthetic antimicrobial agents had defects of insufficient absorptivity in a living body, providing only low bioavailability, and of a low antimicrobial activity against Gram positive microorganisms.

Therefore, development of antimicrobial agents having strong antimicrobial activity against both Gram positive and Gram negative microorganisms, including resistant bacteria, and superior absorptivity in living bodies has been desired.

In view of such a situation, the present inventors have synthesized a number of quinolone derivatives and studied their antimicrobial activity and absorptivity in a living body, and found that quinolone carboxylic acid derivatives of the following formula (1) and their salts exhibited antimicrobial activities against Gram positive microorganisms much stronger than conventional quinolone carboxylic acid derivatives, while maintaining their strong antimicrobial activities against Gram negative microorganisms, as well as excellent absorptivity. Such findings have led to the completion of the present invention.

DISCLOSURE OF THE INVENTION

The present invention provides a quinolone carboxylic acid derivative having the following formula (1), ##STR2## wherein R¹ is a hydrogen atom, an alkyl group, an aralkyl group, or an ester residual group which can be hydrolyzed in living bodies, R² is a hydrogen atom or an amino group which may be substituted by one or two lower alkyl groups, X is a hydrogen atom or a halogen atom, Y is CH₂, O, S, SO, SO₂, or N--R³, wherein R³ is a hydrogen atom or a lower alkyl group, and Z is an oxygen atom or two hydrogen atoms; or a salt thereof.

The present invention also provides an antimicrobial agent comprising a quinolone carboxylic acid derivative of formula (1) or a salt thereof as an effective component.

BEST MODE FOR CARRYING OUT THE INVENTION

Given as examples of groups represented by R¹ in formula (1) are, as alkyl groups, linear or branched alkyl groups having 1-12 carbon atoms, e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, and the like; as aralkyl groups, benzyl, phenyl ethyl, methyl benzyl, naphtyl methyl, and the like; and as ester residual groups which can be hydrolyzed in living bodies, alkanoyloxyalkyl, alkoxycarbonyloxyalkyl, carbamoylalkyl, alkoxyalkyl, and the like; specifically, acetoxymethyl, 1-acetoxyethyl, ethoxycarbonyloxymethyl, carbamoylmethyl, carbamoylethyl, methoxymethyl, methoxyethyl, and the like. Examples of amino groups which may be substituted by one or two lower alkyl groups, represented by R², include amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, diisopropylamino, and the like. Examples given of halogen atoms represented by X are chlorine, fluorine, bromine, iodine, and the like. Lower alkyl groups used in the present invention may be linear or branched alkyl groups having 1-5 carbon atoms, e.g., methyl, ethyl, i-propyl, sec-butyl, t-butyl, amyl, and the like.

When R² in formula (1) is other than hydrogen, the carbon atom to which R² is bonded is asymmetrical, so that there are optical isomers; R and S compounds, for compounds (1) of the present invention. The present invention includes both the optical isomers and the racemate.

As examples of the salts of the compounds of formula (1) of the present invention, salts of alkali metal, inorganic acid, organic acid, and the like are given, and more specifically, lithium salts, sodium salts, potassium salts, and the like, as salts of alkali metal; hydrochloride, sulfate, nitrate, hydrobromide, phosphate, and the like, as salts of inorganic acids; and acetate, fumarate, maleate, lactate, citrate, tartarate, malate, oxalate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like, as salts of organic acid.

In the preparation of the compound of formula (1) of the present invention [Compounds (1a) and (1b)] Compound (2) and Compound (3), for example, are reacted according to the following reaction scheme to produce Compound (1a), and Compound (1a) is halogenated to produce Compound (1b). ##STR3## wherein X' is a halogen atom, and R¹, R², Y and Z are the same as those previously defined.

The raw material, Compound (2), is a known compound and can be prepared by the method described, for example, in Journal of Medicinal Chemistry, 31, 983 (1989). Compound (3) is also a known compound and can be prepared by the method described, for example, in Journal of American Chemical Society, 106, 630 (1984).

In order to prepare Compound (1a) from Compound (2) and Compound (3), 1 mol of Compound (2) is reacted with 1-5 mols of Compound (3) in a solvent such as acetonitrile, dimethylsulfoxide, or the like at room temperature to 100° C. for 1-7 days. After the reaction, precipitate is collected by filtration and washed with a suitable solvent, e.g., methanol, chloroform, ether, etc., to obtain a crude product. The crude product is purified by silica gel column chromatography or by recrystallization to obtain Compound (1a).

The preparation of Compound (1b) from Compound (1a) can be carried out by a method described, for example, in Japanese Patent Laid-open 90183/1989; that is, 1 mol of Compound (1a) is reacted with 1-10 mols of a halogenizing agent, such as sulfuryl chloride, chlorine, bromine, iodine, N-chlorosuccinic acid imide, N-bromosuccinic acid imide, or the like, in a suitable solvent, such as chloroform, dichloromethane, acetic acid, methanol, ethanol, or the like, at 0°-100° C. for 1-48 hours. After the reaction, water is added to collect precipitate by filtration and the precipitate is washed with water to produce a crude product. This crude product is purified by silica gel column chromatography or by the recrystallization to obtain Compound (1b).

If necessary, Compound (1) thus obtained is converted into a salt, such as a salt of alkali metal, inorganic acid, organic acid, or the like, according to a conventional method.

When Compound (1) of this invention thus prepared is used as an antimicrobial agent, it is administered orally at a dose of 200 to 800 mg per day or parenterally at a dose of 5 to 40 mg per day, depending on the weight, the age, the sex, the physical conditions, or the symptom of the patient or the manner of administration.

Compound (1) can be formed into various antimicrobial preparations, such as tablets, granules, powders, capsules, suspensions, injections, suppositories, or the like, according to conventional methods. When solid preparations are produced, compound (1) is mixed with excipients, and as required, with binders, disintegrators, lubricants, coloring agents, sweetening agents, flavoring agents, fillers, coating agents, sugar-coating agents, and the like, and formed into preparations such as tablets, granules, powders, capsules, suppositories, or the like according to known methods. When compound (1) is made into a preparation for injection, it is dissolved, suspended, or emulsified into an aqueous medium such as distilled water, or made into powder which is dissolvable when it is injected. Intravenous, intraarterial, intraportal, intraperitoneal, intramuscular, or subcutaneous injection are applicable.

EXAMPLES

The present invention is hereinafter described in more detail by way of examples and test examples, which are not intended to be limiting thereof.

EXAMPLE 1 1-Cyclopropyl-6-fluoro-7-(2,3,4,5,6,7-hexahydro-1H-1,4-diazepin-5-one-1-yl)-4-oxoquinoline-3-carboxylic acid (Compound No. 1)

0,265 g of 1-cyclopropyl-6,7-difluoro-4-oxoquinoline-3-carboxylic acid and 0.200 g of 2,3,4,5,6,7-hexahydro-1H-1,4-diazepin-5-one dissolved into 20 ml of acetonitrile and refluxed for 3 days. After cooling, the precipitate was collected by filtration, washed with chloroform, methanol, and ether in this order to obtain 0.300 g of colorless crystals of the target compound (yield: 83%).

IRν_(max) ^(KBr) cm⁻¹ : 1720, 1660 1620 ¹ H-NHR δ ppm(NaOD+D₂ O): 0.76-1.48(m, 4H), 2.50-3.80(m, 9H), 7.10(d, J=7.7 Hz, 1H), 7.56(d, J=14.1 Hz, 1H), 8.48(s, 1H) m.p.: 300° C. or above

EXAMPLE 2 8-Chloro-1-cyclopropyl-6-fluoro-7-(2,3,4,5,6,7-hexahydro-1H-1,4-diazepin-5-one-1-yl)-4-oxoquinoline-3-carboxylic acid (Compound No. 2)

0.84 ml of sulfuryl chloride was added dropwise to a suspension of 1.50 g of 1-cyclopropyl-6-fluoro-7-(2,3,4,5,6,7-hexahydro-1H-1,4-diazepin-5-one-1-yl)-4-oxoquinoline-3-carboxylic acid in 30 ml of chloroform, and the mixture was stirred for 12 hours at room temperature. After an addition of ice water, the precipitate was collected by filtration, washed with water, dried in air, and recrystallized in ethanol-chloroform to obtain 0.87 g pale yellow crystals of the target compound (yield: 53.0%).

IRν_(max) ^(KBr) cm⁻¹ : 1720, 1660 1620 ¹ H-NHR δ (CD₃ OD+CDCl₃): 0.80-1.50(m, 4H), 2.50-3.00(m, 2H), 3.30-3.64(m, 7H), 7.52(s, 1H), 8.10(d, J=11.6 Hz, 1H), 9.02(s, 1H) m.p.: 282°-284° C. (decomposed)

EXAMPLES 3-9

Compound Nos. 3-9 listed in Table 1 were prepared in the same manner as in Example 1. Physicochemical data of these compounds are given in Table 2.

                  TABLE 1                                                          ______________________________________                                          ##STR4##                                                                      Com-                  Com-                                                     pound                 pound                                                    No.    A              No.      A                                               ______________________________________                                                 ##STR5##      7                                                                                        ##STR6##                                       4                                                                                      ##STR7##      8                                                                                        ##STR8##                                       5                                                                                      ##STR9##      9                                                                                        ##STR10##                                      6                                                                                      ##STR11##                                                              ______________________________________                                    

                                      TABLE 2                                      __________________________________________________________________________             Melting                                                                Compound No.                                                                           Point(°C.),                                                                    Property                                                                              IR (KBr, cm.sup.-1)                                                                    .sup.1 H-NMR (δ ppm)                       __________________________________________________________________________     3       268-271                                                                               light yellow                                                                          1720, 1650, 1625                                                                       1.10-1,60(m, 4H), 2.80-3.15(m, 5H),                                            3.40-3.85(m, 7H), 7.44(d, J=7.7Hz,                       (decomposed)                                                                          powder         1H), 7.98(d, J=14.1Hz, 1H), 8.76(s, 1H).                                       (CDCl.sub.3 +CD.sub.3 OD).                       4       205-209                                                                               colorless                                                                             1630    1.00-2.20(m, 10H), 3.00-4.00(m, 6H),                                           7.28(d, J=(.0Hz, 1H), 7.96(d,                                   powder         J=15.4Hz, 1H), 8.76(s, 1H). (CDCl.sub.3                                        +CD.sub.3 OD).                                   5       228-230.5                                                                             light yellow                                                                          1720, 1620                                                                             1.10-1.40(m, 4H), 1.40-2.10(m, 8H),                                            3.05-3.30(m, 1H), 3.30-3.80(m, 4H),                             powder         7.18(d, J=9.0Hz, 1H), 7.90(d, J=15.4Hz,                                        1H), 8.70(s. 1H). (CDCl.sub.3).                  6       184-187                                                                               light yellow                                                                          1720, 1625                                                                             1.00-1.65(m, 4H), 1.65-2.20(m, 6H), 2.32(s,                                    6H), 2.68-3.05(m, 1H), 3.10-                                    powder         3.75(m, 4H), 3.75-4.05(m, 1H), 7.25(d,                                         J=9.6Hz, 1H), 7.90(d, J-15.4Hz,                                                1HO, 8.68(s, 1H). (CDCl.sub.3).                  7       199-203                                                                               light brown                                                                           1720. 1610                                                                             1.00-1.40(m, 4H), 2.50-3.10(m, 4H), 3.10-                                      4.00(m, 10H), 7.39(d, J=7.9Hz,                           (decomposed)  powder  1H), 7.71(d, J=15.2Hz. 1H), 8.54(s, 1H),                                       (DMSO-d.sub.6).                                  8       215-217                                                                               colorless                                                                             1625    1.00-2.20(m, 10H), 3.00-4.00(m, 6H),                                           7.28(d, J=7.7Hz, 1H), 7.96(d,                                   powder         J=15.4Hz, 1H), 8.75(s, 1H). (CDCl.sub.3                                        +CD.sub.3 OD).                                   9       218-221                                                                               colorless                                                                             1725, 1620                                                                             1.00-2.20(m, 10H), 2.60-4.00(m, 6H),                                           7.25(d, J=7.7Hz, 1H), 7.85(d,                                   powder         J=15.4Hz, 1H), 8.75(s, 1H). (CDCl.sub.3                                        +CD.sub.3 OD).                                   __________________________________________________________________________

EXAMPLES 10-16

Reactions were carried out in the same manner as in Example 2 to prepare Compound Nos. 10-16 listed in Table 3. Physicochemical data of these compounds are given in Table 4.

                  TABLE 3                                                          ______________________________________                                          ##STR12##                                                                     Com-                  Com-                                                     pound                 pound                                                    No.    A              No.      A                                               ______________________________________                                         10                                                                                     ##STR13##     14                                                                                       ##STR14##                                      11                                                                                     ##STR15##     15                                                                                       ##STR16##                                      12                                                                                     ##STR17##     16                                                                                       ##STR18##                                      13                                                                                     ##STR19##                                                              ______________________________________                                    

                                      TABLE 4                                      __________________________________________________________________________             Melting                                                                Compound No.                                                                           Point(°C.),                                                                    Property                                                                              IR (KBr, cm.sup.-1)                                                                    .sup.1 H-NMR (δ ppm)                       __________________________________________________________________________     10      136-140                                                                               light yellow                                                                          1720, 1640,                                                                            0.80-1.50(m, 4H), 2.80-3.00(m, 2H), 3.08(s,                                    3H), 3.30-3.80(m, 6H),                                          powder 1610    4.20-4.50(m, 1H), 8.15(d, J=11.6Hz, 1H),                                       9.00(s, 1H), (CDCl.sub.3).                       11      275-278                                                                               colorless                                                                             1610-1640                                                                              0.55-2.30(m, 4H), 1.40-1.95(m, 6H),                                            2.75-3.45(m, 5H), 4.00-4.30(m, 1H),                      (decomposed)                                                                          powder         7.90 (d), J=11.6Hz, 1H), 8.75(s, 1H).                                          (NaOD+D.sub.2 O).                                12      163-165                                                                               light yellow                                                                          1720, 1620                                                                             0.80-1.50(m, 4H), 1.55-2.00(m, 8H),                                            3.20-3.70(m, 4H), 4.24-4.55(m, 1H),                             powder         8.05(d, J=11.6Hz, 1H), 8.96(s, 1M).                                            (CDCl.sub.3).                                    13      210-215                                                                               light yellow                                                                          1720, 1610                                                                             1.00-1.45(m, 4H), 1.60-2.20(m, 6H),                                            2.60-2.80(m, 6H), 3.00-3.60(m, 4H),                      (decomposed)                                                                          powder         3.80-4.00(m, 1H), 4.15-4.30(m, 1H), 8.15(d,                                    J=7.7Hz, 1H), 8.98(s, 1H).                                                     (CDCl.sub.3).                                    14      202-208                                                                               brown  1723, 1630                                                                             0.90-1.30(m, 4H), 2.60-4.20(m, 13H),                                           4.20-4.50(m, 1H), 7.93(d, J=11.0Hz,                      (decomposed)                                                                          powder         1H), 8.81(s, 1H). (DMSO-d.sub.6 ).               15      255-257                                                                               colorless                                                                             1600-1640                                                                              0.50-1.30(m, 4H), 1.40-2.00(m, 6H),                                            2.75-3.50(m, 5H), 4.00-4.30(m, 1H),                      (decomposed)                                                                          powder         7.90(d, J=11.6Hz, 1H), 8.65(s, 1H),                                            (NaOD+D.sub.2 0).                                16      241-244                                                                               colorless                                                                             1600-1640                                                                              0.50-1.30(m, 4H), 1.40-2.00(m, 6H),                                            2.80-3.50(m, 5H), 4.10-4.40(m, 1H),                      (decomposed)                                                                          powder         7.90(d, J=11.6Hz, 1H), 8.65(s, 1H),                                            (NaOD+D.sub.2 0).                                __________________________________________________________________________

EXAMPLES 17-21

Reactions were carried out in the same manner as in Example 1 or 2 to prepare Compound Nos. 17-21 listed in Table 5. Physicochemical data of these compounds are given in Table 6.

                  TABLE 5                                                          ______________________________________                                          ##STR20##                                                                     Com-                      Com-                                                 pound                     pound                                                No.    A           X.sup.1                                                                               No.   A         X.sup.1                              ______________________________________                                         17                                                                                     ##STR21##  H      20                                                                                    ##STR22##                                                                               Cl                                   18                                                                                     ##STR23##  H      21                                                                                    ##STR24##                                                                               Cl                                   19                                                                                     ##STR25##  H                                                           ______________________________________                                    

                                      TABLE 6                                      __________________________________________________________________________             Melting                                                                Compound No.                                                                           Point(°C.),                                                                    Property                                                                              IR (KBr, cm.sup.-1)                                                                    .sup.1 H-NMR (δ ppm)                       __________________________________________________________________________     17      231-233                                                                               light yellow                                                                          1720, 1625                                                                             1.10-1.40(m, 4H), 1.80-2.20(m, 2H),                                            2.50-2.70(m, 2H), 2.80-3.10(m, 2H),                             powder         3.60-4.00(m, 5H), 7.33(d, J=7.9Hz. 1H),                                        7.80(d, J=15.4Hz, 1HY), 8.58(s,                                                1H), (DMSO-d.sub.6).                             18      238-239                                                                               light brown                                                                           1712, 1625                                                                             1.10-1.40(m, 4H), 1.8-2.2(m, 2H),                                              3.6-4.0(m, 9H), 7.38(d, J=8.1Hz, 1H), 7.81                      powder         (d. J=14.7Hz, 1H), 8.59(s, 1H).                                                (DMSO-d.sub.6).                                  19             colorless      0.60-1.20(m, 4H), 2.20-3.40(m, 9N), 7.10(d,                                    J=8.0Hz, 1H), 7.60(d,                                           plate          J=15.0Hz, 1H), 8.50(s, 1H). (DMSO-d6).                          crystals                                                        20             yellow         0.80-1.40(m, 4H), 1.80-2.20(m, 2H),                                            2.80-4.20(m, 10H; 1H disappeared                                powder         with D.sub.2 0);8.09(d, J=10.8Hz, 1H),                                         8.93(s, 1H).                                                                   (CDCl.sub.3).                                    21      181-183                                                                               colorless                                                                             1726, 1602                                                                             0.80-1.40(m, 4H), 1.60-1.90(br, 1H;                                            disappeared with D.sub.2 0), 1.90-2.30(m,                       needles        2H), 3.40-3.70(m, 4H), 3.70-4.10(m, 4H),                                       4.20-4.50(m, 1H), 8.03(d,                                                      J=11.0Hz, 1H), 8.91(s, 1H).                      __________________________________________________________________________                                   (CDCl.sub.3).                               

Test Example 1

Antimicrobial Activity

Antimicrobial activities against bacteria listed in Tables 7-9 were measured according to the MIC measurement method of The Japan Chemotherapeutic Association. Ofloxacin was used as a control. The results are shown in Tables 7-9.

Medium: Mueller Hinton Medium

Sample dilution: A 1,000 mcg/ml solution in 25% dimethylsulfoxide was prepared. A series of solutions with various concentrations (100 mcg to 0.006 mcg) were prepared by successively diluting the solution with sterilized water by a factor of 1/2.

Amount of inoculated bacteria: 10⁶ /ml

Cultivation conditions: 37° C., 48 hours

Determination: after 24 hours

                  TABLE 7                                                          ______________________________________                                                        MIC (μg/ml)                                                                   Compound  Compound  Oflox-                                    Tested Bacteria  Number 2  Number 15 acin                                      ______________________________________                                         Gram-positive bacteria                                                         1.  Bacillus subtilis                                                                               0.024      0.024  0.098                                       ATCC 6633                                                                  2.  Staphylococcus aureus                                                                           0.012     0.012    0.195                                      FDA 209P                                                                   3.  Staphylococcus aureus                                                                           0.098     0.195   0.78                                        Terajima                                                                   4.  Staphylococcus aureus                                                                           0.012     0.024   0.39                                        Smith                                                                      5.  Staphylococcus epidermidis                                                                      0.049     0.049   0.78                                        ATCC 12228                                                                 6.  Sarcina lutea    0.195     0.098   3.12                                        ATCC 9341                                                                  7.  Streptococcus faecalis                                                                          0.195     0.195   1.56                                        IFO 12964                                                                  8.  Micrococcus lysodeikticus                                                                       0.049     0.195   1.56                                        IFO 3333                                                                   ______________________________________                                    

                  TABLE 8                                                          ______________________________________                                                       MIC (μg/ml)                                                                   Compound  Compound                                             Tested Bacertia Number 2  Number 15 Ofloxacin                                  ______________________________________                                         Gram-negative bacteria                                                         9.  Escherichia coli O-1                                                                           0.195     0.098   0.098                                    10. Escherichia coli K-12                                                                          0.39      0.098   0.098                                    11. Salmonella typhi TD                                                                            0.098     0.049   0.024                                    12. Shigella flexneri 2b                                                                           0.003     0.006   0.012                                    13. Pseudomonas aeruginosa                                                                         6.25      1.56    1.56                                         IFO 13736                                                                  14. Pseudomonas aeruginosa                                                                         12.5      1.56    0.78                                         P2                                                                         15. Pseudomanas aeruginosa                                                                         6.25      0.78    3.12                                         IFO 12582                                                                  16. Klebsiella pneumonias                                                                          0.012     0.012   0.024                                        ATCC 10031                                                                 17. Klebsiella pneumonias                                                                          0.098     0.049   0.024                                        IFO 13541                                                                  18. Proteus vulgaris OXK                                                                           0.024     0.049   0.049                                    19. Proteus rettgeri                                                                               0.78      0.195   0.098                                    20. Serratia marcescens NHL                                                                        0.78      0.195   0.049                                    ______________________________________                                    

                  TABLE 9                                                          ______________________________________                                                      MIC (μg/ml)                                                                   Compound  Compound                                              Tested Bacteria                                                                               Number 2  Number 15 Ofloxacin                                   ______________________________________                                         Mesitylene-resistant streptococcus aureus gram-positive bacteria               21.  M.R. Staphylococcus                                                                          0.049     0.049   0.39                                           aureus 395                                                                22.  M.R. Staphylococcus                                                                          0.024     0.024   0.39                                           aureus 415                                                                23.  M.R. Staphylococcus                                                                          0.024     0.024   0.39                                           aureus 419                                                                24.  M.R. Staphylococcus                                                                          0.024     0.049   0.39                                           aureus 420                                                                25.  M.R. Staphylococcus                                                                          0.024     0.049   0.39                                           aureus 421                                                                ______________________________________                                    

Industrial Applicability

The compound (1) and its salt of this invention exhibit a superior antimicrobial activity, especially against Gram positive microorganisms, and are thus useful for the treatments and prevention of various infectious diseases in clinics. 

We claim:
 1. A quinolone carboxylic acid derivative having the formula (I), ##STR26## wherein Z is an oxygen atom, Y is N--R³, wherein R³ is a hydrogen atom or a lower alkyl group, R¹ is a hydrogen atom, an alkyl group, an aralkyl group, or an ester residual group which can be hydrolyzed in living bodies, R² is a hydrogen atom or an amino group which may be substituted by one or two lower alkyl groups and X is a hydrogen atom or a halogen atom; or a salt thereof.
 2. The quinolone carboxylic acid derivative of claim 1, wherein Z is an oxygen atom, Y is NH, R¹ is a hydrogen atom, R² is hydrogen atom, and X is a hydrogen atom or a halogen atom; or a salt thereof.
 3. The quinolone carboxylic acid derivative of claim 1, wherein X is a chlorine atom.
 4. The quinolone carboxylic acid derivative of claim 2, wherein X is a chlorine atom.
 5. The quinolone carboxylic acid derivative of claim 1, wherein R³ is a hydrogen atom or a C₁ -C₅ -alkyl group.
 6. The quinolone carboxylic acid derivative of claim 1, wherein R² is a hydrogen atom or an amino group which may be substituted by one or two C₁ -C₅ -alkyl groups.
 7. The quinolone carboxylic acid derivative of claim 1, wherein R¹ is a hydrogen atom; a C₁ -C₁₂ -alkyl group; an aralkyl group selected from the group consisting of benzyl, phenylethyl, methylbenzyl, and naphthylmethyl; or an ester residual group which can be hydrolyzed in living bodies.
 8. The quinolone carboxylic acid derivative of claim 1, wherein R³ is a hydrogen atom or a C₁ -C₅ -alkyl group, R¹ is a hydrogen atom; a C₁ -C₁₂ -alkyl group; an aralkyl group selected from the group consisting of benzyl, phenylethyl, methylbenzyl, and naphthylmethyl; or an ester residual group which can be hydrolyzed in living bodies, and R² is a hydrogen atom or an amino group which may be substituted by one or two C₁ -C₅ -alkyl groups.
 9. An antimicrobial composition, comprising an antimicrobially effective amount of a quinolone carboxylic acid derivative of formula (I) ##STR27## wherein Z is an oxygen atom, Y is N--R³, wherein R³ is a hydrogen atom or a lower alkyl group, R¹ is a hydrogen atom, an alkyl group, an aralkyl group, or an ester residual group which can be hydrolyzed in living bodies, R² is a hydrogen atom or an amino group which may be substituted by one or two lower alkyl groups and X is a hydrogen atom or a halogen atom; or a salt thereof, and a pharmaceutically acceptable carrier.
 10. The composition of claim 9, wherein Z is an oxygen atom, Y is NH, R¹ is a hydrogen atom, R² is a hydrogen atom, and X is a hydrogen atom or a halogen atom; or a salt thereof.
 11. The composition of claim 9, wherein X is a chlorine atom.
 12. The composition of claim 10, wherein X is a chlorine atom.
 13. The composition of claim 9, wherein R³ is a hydrogen atom or a C₁ -C₅ -alkyl group.
 14. The composition of claim 9, wherein R² is a hydrogen atom or an amino group which may be substituted by one or two C₁ -C₅ -alkyl groups.
 15. The composition of claim 9, wherein R¹ is a hydrogen atom; a C₁ -C₁₂ -alkyl group; an aralkyl group selected from the group consisting of benzyl, phenylethyl, methylbenzyl, and naphthylmethyl; or an ester residual group which can be hydrolyzed in living bodies.
 16. The composition of claim 9, wherein R³ is a hydrogen atom or a C₁ -C₅ -alkyl group, R¹ is a hydrogen atom; a C₁ -C₁₂ -alkyl group; an aralkyl group selected from the group consisting of benzyl, phenylethyl, methylbenzyl, and naphthylmethyl; or an ester residual group which can be hydrolyzed in living bodies, and R² is a hydrogen atom or an amino group which may be substituted by one or two C₁ -C₅ -alkyl groups.
 17. A method for curing an infectious disease caused by a microorganism, comprising administering to a patient in need thereof an effective amount of a quinolone carboxylic acid derivative of the formula (I) ##STR28## wherein Z is an oxygen atom, Y is N--R³, wherein R³ is a hydrogen atom or a lower alkyl group, R¹ is a hydrogen atom, an alkyl group, an aralkyl group, or an ester residual group which can be hydrolyzed in living bodies, R² is a hydrogen atom or an amino group which may be substituted by one or two lower alkyl groups and X is a hydrogen atom or a halogen atom; or a salt thereof.
 18. The method of claim 17, wherein Z is an oxygen atom, Y is NH, R¹ is a hydrogen atom, R² is a hydrogen atom, and X is a hydrogen atom or a halogen atom; or a salt thereof.
 19. The method of claim 17, wherein X is a chlorine atom.
 20. The method of claim 18, wherein X is a chlorine atom.
 21. The method of claim 17, wherein R³ is a hydrogen atom or a C₁ -C₅ -alkyl group.
 22. The method of claim 17, wherein R² is a hydrogen atom or an amino group which may be substituted by one or two C₁ -C₅ -alkyl groups.
 23. The method of claim 17, wherein R¹ is a hydrogen atom; a C₁ -C₁₂ -alkyl group; an aralkyl group selected from the group consisting of benzyl, phenylethyl, methylbenzyl, and naphthylmethyl; or an ester residual group which can be hydrolyzed in living bodies.
 24. The method of claim 17, wherein R³ is a hydrogen atom or a C₁ -C₅ -alkyl group, R¹ is a hydrogen atom; a C₁ -C₁₂ -alkyl group; an aralkyl group selected from the group consisting of benzyl, phenylethyl, methylbenzyl, and naphthylmethyl; or an ester residual group which can be hydrolyzed in living bodies, and R² is a hydrogen atom or an amino group which may be substituted by one or two C₁ -C₅ -alkyl groups. 